Plasma high density lipoproteins (HDL) are a major protective factor in atherosclerosis. The mechanisms of[unreadable] the protective effect of HDL are incompletely understood. Mutations in ABCA1 result in low HDL and[unreadable] impaired efflux of cholesterol from macrophage foam cells to lipid-poor apoA-l. However, while ABCA1 plays[unreadable] a key role in HDL formation, ABCA1 interacts poorly with HDL particles that form the bulk of plasma HDL.[unreadable] This observation led to our recent discovery that two LXR-induced half-transporters, ABCG1 and ABCG4,[unreadable] mediate cholesterol efflux to HDL particles but not to lipid-poor apoA-l. ABCG1 is primarily responsible for[unreadable] cholesterol efflux to HDL in LXR-activated macrophages. The primary hypothesis of this project is that the[unreadable] activity of ABCG1 mediates the protective effect of HDL by promoting efflux of cholesterol from macrophages[unreadable] and possibly other vascular cells to HDL. A secondary hypothesis is that changes in cellular cholesterol[unreadable] efflux or distribution mediated by ABCG1 inhibit cholesterol-induced cell death, an idea we will explore[unreadable] collaboratively with Dr.Tabas. In Aim 1, we will evaluate the cellular mechanisms of cholesterol efflux[unreadable] mediated by ABCG1 and the role of ABC transporters in preventing cholesterol-induced apoptosis. In Aim 2[unreadable] the role of ABCG1 in vivo will be evaluated in gene knock-out mice and effects on atherosclerosis will be[unreadable] determined in atherosclerosis-susceptible backgrounds. In Aim 3, the function of ABCG1 in macrophages[unreadable] and hepatocytes will be evaluated by development of conditional knock-outs. The specific roles of ABCG1[unreadable] and ABCA1 in HDL protection will be evaluated by seeing if the protective effect of increased HDL levels[unreadable] resulting from apoA-l overexpression is reduced in a setting of macrophage ABCG1 and/or ABCA1[unreadable] deficiency. The results of these studies will be directly relevant to new treatments aiming to reduce[unreadable] atherosclerosis by increasing HDL levels.